Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach

• Published in: European journal of medicinal chemistry 2020-09, Vol.201, p.112461-112461, Article 112461
• Main Authors: Azimian, Fereshteh, Hamzeh-Mivehroud, Maryam, Shahbazi Mojarrad, Javid, Hemmati, Salar, Dastmalchi, Siavoush
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis - drug effects; Catalytic Domain; Cell Line, Tumor; Cell Proliferation - drug effects; de novo drug design; Diaryl urea; Docking; Drug Screening Assays, Antitumor; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; Lead optimization; MAP Kinase Signaling System - drug effects; Molecular Docking Simulation; Molecular Structure; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - metabolism; Phenylurea Compounds - pharmacology; Protein Binding; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology; Sorafenib - pharmacology; Structure-Activity Relationship; Synthesis; Vascular Endothelial Growth Factor Receptor-2 - chemistry; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112461

To develop inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was generated and expanded. Considering in silico binding affinity towards VEGFR2, synthetic feasibility, and drug-likeness property, some of the designed ligands were selected for synthesis and screening for their in vitro antiproliferative activities against two cancer cell lines (HT-29 and A549). Four compounds (13a, 14a, 14l and 15b) exhibited stronger antiproliferative activity (with IC50 values of 13.27, 6.62, 12.74, 3.38 μM, respectively) against HT-29 cells compared to that of the positive reference drug sorafenib (IC50 = 17.28 μM). Notably, compound 15b demonstrated the highest activity, and in particular, it induced HT-29 apoptosis, increased intracellular reactive oxygen species level, arrested cell cycle at G0/G1 phase, and influenced the expression of apoptosis- and cell cycle-related proteins. 15b compound can effectively block the Raf/MEK/ERK pathway and inhibit VEGFR2 phosphorylation. Molecular docking revealed that 15b can bind well to the active site of VEGFR2 receptor. Collectively, 15b may be considered as a promising compound amenable for further investigation for the development of new anticancer agents. [Display omitted] •De novo structure-based lead optimization was used to design novel sorafenib-like anticancer agents.•The designed diaryl urea compounds were synthesized and characterized.•Molecular and cellular mechanisms of the most potent antiproliferative derivative 15b were investigated.•Docking study was carried out to explore the binding modes of compound 15b with VEGFR2.